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2013 Grants - Granholm

BDNF and Executive Dysfunction in Down Syndrome

Anne-Charlotte Granholm, Ph.D.
Medical University of South Carolina
Charleston, South Carolina

Down Syndrome/Alzheimer's Disease Investigator-Initiated Program

People with Down syndrome carry a high risk for Alzheimer's disease and other dementias. One characteristic brain change in Down syndrome is the loss of cells called noradrenergic neurons. These cells are known to support important cognitive abilities, including executive function (or the ability to carry out, "execute", daily tasks). The loss of such cells in Down syndrome may help explain why individuals with Down syndrome are at a high risk for dementia.

Anne-Charlotte Granholm, Ph.D., and colleagues hope to clarify the role of noradrenergic neuron damage in people who have both Down syndrome and Alzheimer's. For their effort, they will use mice genetically altered to develop symptoms of both diseases. The investigators will inject their mice with special proteins called "designer" receptors. Receptors occur naturally in the brain, and neurons use them as "docking sites" for sending and receiving chemical signals. Designer receptors are engineered to "attach" themselves to neurons and effectively replace the natural receptors. Once a designer receptor is integrated into a cell and depending on how it is engineered, it can either reduce or enhance that cell's ability to transmit chemical messages—enabling scientists to artificially "turn on" or "turn off" cellular activity in the brain.

Dr. Granholm and colleagues will use designer receptors to increase or decrease the function of noradrenergic neurons in their mice. They will then assess how varying activity levels in these neurons affect the production of brain derived neurotrophic factor (BDNF), a hormone-like molecule known to protect brain health and promote memory. People with Alzheimer's disease and Down syndrome tend to have lower than normal levels of BDNF. The researchers will also assess how noradrenergic cell activity affects executive function in their animals. Results of these efforts could help clarify how various cognitive deficits occur in Down syndrome and Alzheimer's. They could also lead to novel therapies for people with both conditions.